Review Microtubule-Associated Proteins as Targets in Cancer Chemotherapy Kumar M.R. Bhat andVijayasaradhi Setaluri Abstract Natural and synthetic compounds that disrupt microtubule dynamics are among the most successful and widely used cancer chemotherapeutic agents. However,lack of reliable markers that predict sensitivity of cancers to these agents and development of resistance remain vexing issues. There is accumulating evidence that a family of cellular proteins that are associated with and alter the dynamics of microtubules can determine sensitivity of cancer cells to microtubule- targeting agents and play a role in tumor cell resistance to these agents. This growing family of microtubule-associated proteins (MAP) includes products of oncogenes,tumor suppressors, and apoptosis regulators,suggesting that alteration of microtubule dynamics may be one of the critical events in tumorigenesis and tumor progression. The objective of this review is to integrate the knowledge on these seemingly unrelated proteins that share a common function and examine their relevance to microtubule-targeting therapies and highlight MAPs-tubulin-drug interactions as a novel avenue for new drug discovery. Based on the available evidence,we propose that rational microtubule-targeting cancer therapeutic approaches should ideally include proteomic profiling of tumor MAPs before administration of microtubule-stabilizing/destabilizing agents preferentially in combination with agents that modulate the expression of relevant MAPs. Dynamic instability is an essential and indispensable property Microtubules of microtubules. This property is evident most notably during assembly of bipolar spindle and segregation of duplicated Microtubules are essential components of the cytoskeleton chromosomes in mitosis. Several natural and synthetic com- and play a critical role in many cellular processes, including cell pounds that disrupt microtubule dynamics, and hence block division, cell motility, intracellular trafficking, and cell shape mitosis, are currently in use as cancer chemotherapeutic agents. maintenance. Composed of ah-tubulin heterodimers, micro- Variable sensitivity of different cancers and frequent acquisition tubules are intrinsically dynamic polymers, and their dynamic of resistance by others to these agents has prompted a search for property is crucial for the assembly of the mitotic spindle and cellular factors and mechanisms that determine the effective- the attachment and movement of chromosomes along the ness of microtubule-targeting agents (1). A better understand- spindle (2, 3). Suppression of microtubule dynamics by ing of such factors, mechanisms, and their role in conferring microtubule-targeting drugs, such as the Vinca alkaloids and resistance to microtubule-targeting agents is essential for taxanes, can engage the mitotic spindle checkpoint, arresting rational use of highly effective, often toxic, microtubule- cell cycle progression at mitosis and eventually leading to targeting agents for cancer chemotherapy. In this review, we apoptosis (4). These drugs, which are in wide use as cancer synthesize the available knowledge on a seemingly disparate chemotherapeutic agents, generally bind to one of the two group of proteins that, by virtue of binding to microtubules, classes of sites on tubulin, the Vinca domain and paclitaxel site. not only influence the sensitivity of cancer cells to microtubule- Therefore, concerted efforts are ongoing to identify, design, and targeting agents but also seem to be associated with tumor develop agents that bind to these and other sites on tubulin and progression. Proteomic profiles of tumor microtubule-associated alter microtubule dynamics with minimal toxicity to normal proteins (MAP)and an understanding the molecular mecha- tissues. In addition to their direct involvement in the physical nisms that regulate their expression will help design more process of mitosis, microtubules also serve as scaffolds for effective strategies for the use of microtubule-targeting agents in signaling molecules. Thus, sustained modification of signaling cancer chemotherapy. routes and changes in the scaffolding properties of micro- tubules seem to constitute two major processes in the apoptotic response induced by microtubule-interfering agents (reviewed in ref. 5). Authors’ Affiliation: Department of Dermatology,University of Wisconsin School of Medicine,Madison,Wisconsin Cellular Regulation of Microtubule Dynamics Received 12/22/06; revised 1/30/07; accepted 2/20/07. Requests for reprints: Vijayasaradhi Setaluri,Department of Dermatology, Intracellular dynamic behavior of microtubules is regulated University of Wisconsin School of Medicine,1300 University Avenue,B25, by a balance between activities of microtubule-stabilizing and Madison,WI 53706. Phone: 608-263-5362; Fax: 608-263-5223; E-mail: [email protected]. microtubule-destabilizing proteins (6)that include, in various F 2007 American Association for Cancer Research. cell types, a family of MAPs, tau, oncoprotein stathmin/ doi:10.1158/1078-0432.CCR-06-3040 oncoprotein 18, tumor suppressors BRCA1 and pVHL (von www.aacrjournals.org 2849 Clin Cancer Res 2007;13(10) May 15, 2007 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2007 American Association for Cancer Research. Review Hippel-Lindau syndrome)protein and inhibitor apoptosis tau as the most differentially expressed gene that is inversely protein, survivin, and others (Fig. 1). These seemingly unrelated associated with pathologic complete response of breast cancers proteins share a common feature [i.e., they contain tubulin to preoperative paclitaxel chemotherapy. Consistent with its binding domain(s)]. Whereas changes in phosphorylation of function in stabilizing microtubules, loss of tau expression some of these proteins are responsible for cell cycle–specific sensitizes breast cancer cells to the action of paclitaxel. This alterations of the microtubule network, changes in levels of suggests that breast cancer patients may be selected for expression others seem to correlate with aggressiveness of a paclitaxel therapy based on low tau expression, and that variety of human cancers and/or their sensitivity to microtubule- inhibition of tau could be a strategy to make tumors sensitive targeting chemotherapeutic agents. This property of MAP to paclitaxel. Although tau is a promising marker of sen- binding to tubulin and altering microtubule dynamics in the sitivity to paclitaxel, other mechanisms and pathways of context of tumor sensitivity to microtubule-targeting agents acquiring resistance to microtubule-targeting agents need to be provides an opportunity to manipulate MAP-tubulin interac- considered. tions to affect tubulin-drug interactions and clinical outcome in MAP2. MAP2 is found primarily in the dendritic exten- cancer chemotherapy. sions of post-mitotic, terminally differentiated neurons. MAP2 plays a critical role in neurite outgrowth and dendrite devel- MAPs opment (reviewed in ref. 10). Among neuronal MAPs, MAP2 expression is considered a hallmark of neuronal differentiation MAPs are a family of proteins that bind to and stabilize (11). Consistent with its microtubule-stabilizing function, microtubules. Whereas MAP4 is expressed ubiquitously, iso- expression of MAP2 in nonneuronal cells results in rapid forms of MAP1 and MAP2 are expressed primarily in neurons, formation of stable microtubule bundles and dendrite-like and MAP7 is restricted to epithelial cells (7). Aberrant processes (12). expression of MAPs and their relevance to the resistant Variable MAP2 immunoreactivity is found in most pulmo- phenotype of a wide range of malignancies to microtubule- nary neuroendocrine carcinomas and in some non–small-cell targeting agents have been documented. carcinomas (13), whereas Merkel cell carcinomas show diffuse Tau. Tau is one of the most extensively investigated MAP. It to focal MAP2 expression. MAP2 is thought to be a valuable is found primarily in neurons, where its phosphorylated ancillary marker in skin tumors suspicious of neuroendocrine isoforms bind to tubulin to promote polymerization and origin (14). An inducible, high molecular weight isoform of stabilization of axonal microtubules. Abnormal phosphoryla- MAP2 has been proposed as a diagnostic marker in oral tion of tau is associated with Alzheimer’s disease and other squamous cell carcinoma (15). neurodegenerative disorders known as tauopathies (8). Fang et al. (16)described induction of juvenile and adult Expression of tau in nonneuronal tissues, including breast isoforms of MAP2 in cultured metastatic melanoma cells and cancer cells, has been reported (9). Rouzier et al. (9) identified their expression in benign and primary malignant melanomas. Focal expression of MAP2 was found only in a few metastatic melanomas. Kaplan-Meier survival and multivariate Cox regression analysis showed that patients diagnosed with MAP2+ primary melanomas have significantly better metastatic À disease-free survival than those with MAP2 disease. Investiga- tion of the mechanisms that underlie the effect of MAP2 on melanoma progression showed that MAP2 expression in metastatic melanoma cells leads to microtubule stabilization, cell cycle arrest in G2-M phase, and growth inhibition in vitro and in vivo. These data suggest that activation of microtubule- stabilizing proteins in primary cancer cells may inhibit their proliferation and correlate with a delay or inhibition of metastasis (17). Moreover, the ability to induce/up-regulate